1. Field of the Invention
The invention relates to methods and compositions for encouraging bone regeneration, especially after tooth loss, using non-steroidal anti-inflammatory drugs (NSAIDs).
2. Description of Related Art
Removing a tooth in dentistry can have consequences that extend far beyond the loss of the tooth. Resorption of the residual alveolar ridge that formerly supported the tooth is a chronic localized process that occurs following tooth extraction. This bone loss can affect nearby, healthy teeth and can increase the difficulty of fitting dentures and supporting other replacement dental work. Although the rate of bone loss is most rapid shortly after tooth extraction, resorption may continue long after the extraction.
Removing a tooth for the purpose of fitting full or partial dentures is a procedure that can often be planned in advance. Therapy can begin even before removal of the tooth or teeth. Extraction mandated by trauma or other emergency conditions, however, often cannot be planned far in advance, so pre-extraction therapy is not always possible.
Resorption is an especially difficult problem for fitting dentures. Stability, retention, function and the aesthetics of removable dentures are directly affected by alveolar ridge size and shape. Thus, resorption is an important factor in determining the longevity and clinical outcome of a removable denture.
Bone resorption is also a difficult problem around dental implants, particularly during the initial loading period.
Often, two different types of dentures are used with a patient. An "immediate" denture is a removable denture inserted on the day of tooth extraction. Its purpose is to restore function and alleviate the embarrassment that can occur when the patient is forced to endure an extended period of time without teeth. "Conventional" dentures are fitted later, after initial healing, and are intended to be longer-lasting. Bone loss can have a deleterious effect on the fit and efficacy of both types of dentures. Immediate dentures may need to be refitted by the dentist as soon as a few months after the extraction, and conventional, permanent dentures may need frequent monitoring and alteration or replacement.
Although many dentists do nothing at all to forestall bone loss, those that do treat bone loss after extraction do so by placing a material in the post-extraction socket that at least discourages resorption. These materials include bone from cadavers, hydroxyapatite, and specially processed glass particles.
Bone is difficult to work with and, if not properly treated, can carry disease vectors from the donor. Hydroxyapatite is difficult to work with and tends to migrate away from the site. Bioactive glass is an intriguing new product on the market and, although it does not suffer from the problems of the other materials, it has not yet gained wide acceptance in the dental market.
Implanted materials have one additional drawback. At best, the materials act as a matrix for bone growth. They do nothing to reduce or eliminate the forces that cause resorption in the first place. Thus there is still a need in the art for a material that, either alone or in combination with an implanted material, acts to reduce the forces that encourage bone resorption after tooth extraction. A special need remains in the art for a bone-loss therapy that can be administered during or after tooth loss, in those instances when pre-extraction therapy is unavailable.
Various studies have been carried out on bone formation using non-steroidal anti-inflammatory drugs as agents affecting bone growth and bone structure. One article, Yazdi, M. et al., "Effects of nonsteroidal anti-inflamatory drugs on Demineralized Bone-induced Bone Formation," J. Periodont Res 1992; 27:28-33, reported the effects of acetylsalicylic acid, acetarninophen, ibuprofen, indomethacin, prioxicam and flurbiprofen on bone growth over powdered demineralized bone implanted into para-sternal sites on rats. The various additives (as well as the control) were injected into the rats in a single daily subcutaneous injection beginning either three days prior to implantation or three days after implantation. The researchers reported that both inhibitory and stimulatory effects on bone formation were found in rats treated before implantation. Despite some encouraging pictures in the article, the researchers concluded that pretreating with flurbiprofen "did not appear to significantly affect bone formation," id. at 31, while pretreatment with ibuprofen appeared to enhance bone formation. Id. at 31-32. Treating with NSAIDS after implantation, however, did not appear to affect the rats, "Wile no significant differences between experimental and control groups were observed, there was good osteoinduction in groups treated with indomethacin . . . piroxicam . . . or flurbiprofen . . . " Id. at 32.
Another research group studied the effects of systemic flurbiprofen on dental implants, Jeffcoat, M. et al., "The Effect of Systemic Flurbiprofen on Bone Supporting Dental Implants," JADA, Vol. 126, March 1995, 305-11. The group noted that flurbiprofen, along with others, had shown the ability to retard alveolar bone loss due to periodontitis but that the effect of NSAIDS on preventing bone loss in implant situations had not been established. The researchers studied the effect of a course of systemic administration of flurbiprofen on titanium implants using 50 and 100 mg doses of flurbiprofen. The high dose flurbiprofen dosage reduced bone loss, but showed no increase in bone levels, except for a brief increase in bone mass after three months that subsequently disappeared. The researchers concluded, "At first glance, the hypothesis underlying the effect(s) of NSAIDs on bone may appear deceptively straightforward. However, the basic pathophysiology underlying these agents could be used to support either positive or negative effects on bone." Id. at 310.